After posting the talks that Bob Blaskiewicz and I gave at TAM this year, I realized that it’s been a while since I’ve written about the topic of those talks, namely Stanislaw Burzynski, the Houston cancer doctor who inexplicably has been permitted to continue to administer an unproven cancer treatment to children with deadly brain cancers for nearly 37 years now. Beginning in 1977, when he left Baylor College of Medicine and opened up the Burzynski Clinic, Burzynski has administered a cancer therapy that he calls antineoplastons to patients. After nearly four decades and several dozen phase II clinical trials started, he has never published a completed phase II trial. The only evidence he’s published consists mainly of cell culture studies, case reports, and couple of preliminary reports of his phase II clinical trials. Of course, Burzynski’s lawyer, Richard Jaffe, even dismissively admitted that these clinical trials are designed solely to allow Burzynski to keep giving antineoplastons.

All of this is why those of us who follow Burzynski have been waiting with the proverbial bated breath to find out what the FDA concluded. Just before the government shutdown the first shoe dropped, when the FDA released a warning letter to the Burzynski Research Institute (BRI). Then last week, the second shoe dropped, when the FDA released the original forms describing its findings regarding the inspection. The findings are, to put it mildly, damning in the extreme. In fact, now, more than ever, I wonder how on earth Burzynski has been allowed to continue to run clinical trials—or even practice—for so long. The findings include massive deficiencies in the Burzynski institutional review board (IRB), the committee responsible for making sure that regulations designed to protect human subjects in research are adhered to.

Before looking at the new FDA findings, let’s recap what is known about Burzynski’s IRB. First, we know that the IRB is headed by Carlton F. Hazlewood, PhD, who just so happens to be on the board of directors of the Burzynski Research Institute. As I noted before, given that the Burzynski Clinic has been trying for decades to commercialize antineoplastons, this is a profound conflict of interest. I also ask you to think of it this way again: What would Burzynski’s defenders say if they found out that a sitting member of the board of directors of Merck, for example, was serving on the IRB that oversees Merck’s clinical trials? Having Hazlewood serve on the BRI IRB is the same thing. True, it’s not quite as bad as having the principal investigator of a study chair the IRB overseeing his studies, as Mark Geier has done, but it’s pretty bad. Again, one wonders how Burzynski supporters would react if pharmaceutical companies or even research institutes trying to commercialize a discovery made by their investigators allowed high ranking leadership sit on their IRBs.

Last year, a certain “friend” of mine had discussed the problems with Burzynski’s IRB before, and these notes simply amplify and add detail to the problems that were already known. These notes suggest how Burzynski uses his IRB to get around some of the restrictions that were placed on him using antineoplastons. As you might recall, the Common Rule demands that all clinical trials by investigators whose institutions receive federal funding or that are being done in order to win FDA approval for a drug or device must be overseen by an IRB, whose purpose is to protect the human subjects who take place in the trials. This is an absolutely essential purpose of the IRB, its key reason for existence. It is not there to evaluate the science, except to the extent that badly designed clinical trials based on bad science endanger human subjects. Its purpose is to make sure that the risks and benefits of clinical trials are reasonably balanced, make sure that patients entering clinical trials receive adequate informed consent, and to keep an eye on the trial as it is being carried out, evaluating adverse event reports and, if necessary, shutting the trial down if there are too many or if one group starts doing too poorly relative to the other.

Failure to keep a copy of the study protocol and informed consent form.

Failure to receive and/or require progress reports from the principal investigator for the study.

Failure to receive and/or require a final report from the principal investigator for the study prior to removal from the IRB’s active list of studies.

Failure to assure that FDA approval was obtained by the principal investigator for the study prior to the treatment of a patient under a special exception.

Approval of special exceptions via expedited review.

The IRB approved research without determining that the following criteria were met: That risks to subjects were minimized and that risks to subjects were reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result.

The IRB failed to prepare, maintain, and follow written procedures for conducting its initial and continuing review of research.

The IRB failed to ensure that informed consent would be sought from each prospective subject or the subject’s legally authorized representative.

The IRB failed to ensure that no member participated in the initial or continuing review of a project in which the member had a conflicting interest.

The IRB failed to conduct continuing reviews.

The latest round of findings from the FDA’s most recent investigation eight months ago reads like an acid flashback of investigations past. According to the FDA warning letter based on this FDA Form 483, covering the inspection dates from January 22 to February 7, 2013, here’s what the FDA dinged Burzynski for this time. The CliffsNotes version is this:

The IRB approved research without determining that the following criteria were met: risks to subjects were minimized [21 CFR 56.111(a)(1)]; risks to subjects were reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result [21 CFR 56.111(a)(2)].

The IRB failed to determine at the time of initial review that studies involving children are in compliance with 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations [21 CFR 56.109(h)]. This is a repeat violation from our 2010 inspection.

The IRB failed to prepare, maintain, and follow written procedures and maintain adequate documentation governing the functions and operations of the IRB [21 CFR 56.108(a), 21 CFR 56.108(b), and 21 CFR 56.115(a)(6)].

More detailed observations can be found in the Form 483. Basically, the Burzynski Clinic and BRI ran roughshod over human subjects protection. Most of the violations are fairly simple, even for lay people, to understand. For example, not making sure that patients enrolled on clinical trials meet the inclusion criteria, not reporting adverse events in a timely fashion, and not removing patients with adverse events from the study quickly are all fairly self-evident violations and not difficult to explain. It’s fairly easy to understand why failing to remove a patient who suffers an adverse event that the protocol says should be a reason to remove the patient from the protocol is a violation. One violation, however, is not as easy to understand for those not involved in clinical trials and therefore deserves a bit more discussion. I’m referring to Burzynski’s apparent abuse of the expedited approval process through his IRB. This seems to be the “theme” that ties together much of what is reported in this warning letter to the BRI; so I feel the need to explain a bit, in order to put it all into some context.

Quite reasonably, the Office for Human Research Protections (OHRP), the office in the Department of Health and Human Services that oversees IRBs, does not require the same sort of approval process for every sort of human subjects research. Not every study that involves human subjects research is a randomized clinical trial. For instance, in the case of human subjects research that involves pre-existing samples that have been de-identified can be exempted from full IRB review and oversight because, well, there are no human subjects to be endangered, even through linking of their identities to a specimen demonstrating a disease. Lots of research gets done this way, for example analyzing or staining pre-existing samples looking for a biomarker or a change in expression of a protein. I’ve done projects like this. This is commonly known as Exemption 4, and there are several other exempt categories.

However, Burzynski doesn’t abuse the exemption process, which, let’s face it, would be very hard to abuse for the most part. What he appears to have abused is the expedited approval process. The expedited review process generally involves approving things like minor revisions to research protocols and informed consent forms. “Expedited” generally means just that: Expedited. A full IRB review is not done, and a streamlined, faster process is used. Expedited approval can also be used for protocols that fall under categories that the Department of Health and Human Services (HHS) deems to be “minimal risk,” described thusly on the University of Kentucky website:

Expedited procedures can only be used to review a study if the only involvement of human subjects fits one or more of the categories specified in the federal regulations and if all of the procedures present no greater than “minimal risk.”

The IRB reviewer confirms that all of the research activities fit in one or more of the expedited categories. If the research includes activities that do not fit in the categories, the study is not eligible for expedited review even if the research involves “minimal risk.”

The Department of Health and Human Services defines minimal risk to mean “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” [45 CFR 46.102(2)(i)].

Investigators are asked to provide a risk assessment, but it is the IRB reviewer’s responsibility to determine whether the research meets the federal definition.

The IRB reviewer must consider two questions:

Is the probability of the harm or discomfort anticipated in the proposed research greater than that encountered ordinarily in daily life or during the performance of routine physical or psychological examinations or tests?

Is the magnitude of the harm or discomfort greater than that encountered ordinarily in the daily life or during the performance of routine physical or psychological examinations or tests?

If the answer is “yes” to either of these questions, then the research does not meet the definition of minimal risk.

A list of the types of research that can be approved through expedited review can be found on the OHRP website. These include things like blood draws, prospective collection of biological specimens by noninvasive means (one could collect urine specimens, for instance, under a protocol approved through the expedited review process), and research involving data that has already been collected. Here’s a hint: Approving “single patient protocols” for an investigational drug that is not FDA-approved does not fall into any of the categories for which expedited review is appropriate, particularly when so many of the patients involved are children and particularly when the drug being tested can cause severe hypernatremia. Basically, from my reading, Burzynski seems to be using the expedited review process to treat patients with antineoplastons who do not qualify for any of his numerous phase II trials, and until last year he was getting away with it. Again, one of the great mysteries is: How?

But that’s not all. The second Form 483 answers a question that many of us interested in Burzynski have wondered about for a very long time.

One mystery solved: What happened to all those complete responses?

There are two central mysteries about Stanislaw Burzynski that I would really, really like to see answered, and, hopefully, I will see them answered soon. The first is, of course: How has he gotten away with it for so many years? The second is: What are his real results? I’m not referring to the results Burzynski and his sycophants claim, but the real results? People like Paul Goldberg and others have been reporting for years that Burzynski’s results don’t seem to match his claims, with cancer experts who have seen some of his actual data reporting that Burzynski’s data “can never be useful to show true merit or lack of merit of his drug” because of an absence of rigorously reported results and independent verification” and “what we have here are bad trials that could never get past peer review of any clinical trials cooperative group.” Indeed, even back in the 1990s, serious adverse reactions were reported, mostly due to the hypernatremia. Now, thanks to these additional two FDA reports (here and here), we finally see a glimmering of light through the shroud of secrecy overlying the Burzynski Clinic.

Much of what is contained in these additional reports overlaps what I discussed before, but there is one kind of violation that does not. It’s a truly egregious violation that I find very difficult to comprehend, given how much it goes against every tenet of clinical research and clinical trials that I’ve been taught and learned over the years. It appears on this Form 483, where it’s discussed under “Observation 1,” and this other Form 483, where it’s discussed under “Observation 1” and “Observation 2.” The brief versions are stated either as “Failure to monitor the progress of an investigation under your IND”; “an investigation was not conducted in accordance with the signed statement of investigator and investigational plan”; or “failure to prepare or maintain adequate case histories with respect to observations and data pertinent to the investigation.” What does this mean? Basically, it means that the BRI misclassified tumor responses to therapy and adverse reactions. Worse, records that would allow the validation of responses to therapy are missing.

Before I get more specific, let me just briefly review what I mean by tumor response. Whenever a drug is given to treat a tumor, the response is the degree of tumor shrinkage that occurs in response to the treatment. In general, there are four categories of results defined and reported in clinical trials of new chemotherapeutic agent:

Complete response (CR): The tumors shrink away to the point that they are no longer detectable by physical examination, imaging studies (MRI, CT scan, etc.), or tumor markers. Obviously, this is the best possible result. This is further divided into a pathological complete response, which means that there are no detectable tumor cells in the resected tumor specimen. Obviously, when this happens, it is a very good thing and a very good prognostic sign. Sadly, it is not seen that often in clinical trials.

Partial response (PR): This is usually defined to mean that the tumors shrink by more than 50% (or, in the case where tumor volume cannot be measured easily, tumor markers fall by more than 50%) in response to therapy but remain detectable. More recent definitions have at times loosened this criterion to include tumors that shrink by 30% or more. Whatever the specific criteria used, a certain degree of tumor shrinkage, or evidence of tumor regression, defined before the clinical trial, must be observed.

Stable disease (SD): The tumors either shrink by less than the criteria for a PR or remain the same size. In some trials, this definition may be broadened to include tumors that increase in size slightly during therapy by less than, depending on the trial, 0-25%, although I’ve personally always been suspicious of calling any detectable growth above random variation in imaging measurements “stable.”

Progressive disease (PD): Tumors increase in size on therapy and/or new metastatic tumors appear. This is obviously strong evidence that in that patient the therapy did not work.

How tumor response is measured varies according to the tumor. Most commonly RECIST criteria are used. For brain tumors, there are criteria other than RECIST that are often used, such as the Macdonald criteria or its update, the RANO criteria. Other methods are being developed, as well. Obviously, there are pros and cons associated with each method. However, when you write a clinical trial, you have to pick one, stick with it, and use it appropriately to classify clinical trial subjects as either having CR, PR, SD, or PD. If these FDA reports are to be believed, Burzynski failed to do that. Worse, he either destroyed, or allowed to be destroyed, the original primary records used to make these determinations.

For example, the FDA notes that:

a. …For 18 of 27 (67%) of subjects, the investigator did not comply with the protocol requirements for assessing the efficacy endpoint of tumor response and recorded inaccurate assessments for tumor response in study records. For example:

b. You did not have a QA monitor properly monitor CRFs [case report forms] and subject records. The investigator destroyed critical subject case history records (target tumor measurement worksheets) or misplaced case history records (original subject CRFs) for all subjects.

Elsewhere, the FDA investigators note:

Your MRI tumor measurements initially recorded at baseline and on-treatment MRI studies for all study subjects were destroyed and are not available for FDA inspectional review.

The other Form 483 goes into a little more detail. Unfortunately, much of what I’d really, really like to know is redacted, specifically how each of these patients didn’t meet one or more of the criteria for the given response level to which Burzynski assigned them. Be that as it may, there’s plenty of damning information in these reports. For example, there are more examples of Burzynski’s failure to report adverse events (i.e., complications or bad things that happened to subjects being treated according to his protocols) in a timely fashion as required by the OHRP and the FDA. For example:

You failed to monitor as required by Section 16 of your Monitoring Plan. The investigator did not report adverse events (AEs) experienced by study subjects, including 18 cases of hypernatremia.

Now let’s look at what I mean when I said that Burzynski misclassified AEs. AEs are graded according to a system known as the Common Terminology Criteria for Adverse Events (CTCAE). The CTCAE is nothing more than a list of AEs and SAEs (serious adverse events) commonly encountered in oncology. Each AE term is defined in the CTCAE and accompanied by a grading scale for severity. The AE terms are also organized by System Organ Classes defined by the Medical Dictionary for Regulatory Activities. The CTCAE is a long list, which can be downloaded as a Microsoft Excel spreadsheet, and it’s been updated several times. The most recent update is v.4.0, released in May 2009. Most of the AEs discussed by the FDA were from before that, so that CTCAE v.3.0 was being used to classify them. AE grades generally range from grade 1 (minor), grade 2 (moderate), grade 3 (severe), grade 4 (potentially life-threatening), to grade 5 (death).

Hypernatremia as I have discussed many times before, is a sodium concentration in the blood that is too high. If the hypernatremia is bad enough, it can be life-threatening. These reports document at least two subjects whose hypernatremia was graded a 2 when it should have been graded a 4. Of course, these two subjects pale in comparison to the number of patients whose hypernatremia either wasn’t reported or wasn’t reported for a long time. For example:

You failed to protect the rights, safety, and welfare of subjects under your care.

Forty-eight (48) subjects experienced 102 investigational overdoses between January 1, 2005 and February 22, 2013, according to the Weekly List of Hospitalizations/SAE [REDACTED] Overdose [redacted]/Catheter Infection report. Overdose incidents have been reported to you on a weekly basis during your Monday, Wednesday, and Friday staff meetings. There is no documentation to show that you have implemented corrective actions during this time period to ensure the safety and welfare of subjects.

This last sentence bears repeating: “There is no documentation to show that you have implemented corrective actions during this time period to ensure the safety and welfare of subjects.” So what we have here is a report finding that not only did Burzynski fail to report in a timely fashion a lot of SAEs, but that he tended to downplay the severity of the ones that he did report. Some AEs weren’t reported until as much as seven years later. Subjects also weren’t removed in a timely fashion for toxicity. For instance, one protocol stated that subjects would be removed after a third episode of Grade 3 or 4 toxicity or any single Grade 4 toxic effect that is “truly life-threatening or is not easily and rapidly reversible.” Of course, one wonders how the IRB could have approved such wording, as there is no distinction between “truly” life threatening and “life threatening” in the definition of Grade 4 toxicity. One patient had seven instances of Grade 3 or 4 toxicity but was not terminated from the trial until over a month after the seventh.

Other violations, although not as egregious, were nonetheless still quite bad. For instance, the informed consent didn’t include a statement of any additional costs to the subject that might result from the research. Several examples of patients who signed the informed consent days to weeks before they signed the billing agreement were presented. In addition, the Burzynski Clinic didn’t keep adequate records of its stocks of antineoplastons and could not account for how much was used by subjects. The number of bags of antineoplastons unaccounted for are truly staggering. One subject had 159 bags unaccounted for. Others ranged from one to 23 bags unaccounted for. Record keeping this sloppy would shut down nearly any clinical trial in and of itself.

The most serious violations of regulations designed to protect human subjects are clearly: (1) the BRI IRB’s misuse of the expedited approval process as an excuse to treat any patient Burzynski wanted to treat; (2) failure to keep original records to document baseline tumor measurements and tumor response; and (3) failure to report AEs and SAEs properly. However, there are a whole bunch of other lesser, but still serious, violations, so many that I find it hard to fathom.

The central mystery of the Stanislaw Burzynski saga

As a translational researcher who frequently works with clinical investigators, I just can’t figure out how Burzynski keeps getting away with it. Either the FDA is more impotent than I had thought, or Burzynski has some serious pull with some powerful people. If my university received even one report like one of the previous FDA reports about Burzynski, it would be quite possible that all federal research funding to the university for biomedical research would be suspended until the university fixed the problems to the satisfaction of the OHRP and FDA. Yet the FDA has found Burzynski to be deficient in numerous areas of human subjects protection multiple times over the last decade. These latest FDA Form 483 reports tell us nothing new, really, other than that Burzynski’s claims of complete responses are very likely nonsense.

If there’s one thing I’ve learned over the years about Brave Maverick Doctors, it’s that they often come to believe that the rules don’t apply to them. They crave the respectability of science, of course, but they are too impatient or too arrogant to play by the rules of science. Unfortunately, that often includes the rules designed to protect human subjects in clinical trials. We’ve seen it before with Mark and David Geier, who formed their own IRB stacked with their cronies. We’ve now seen it with Stanislaw Burzynski, who formed his own IRB. In the world of these Brave Maverick Doctors, the IRB apparently exists not to protect human subjects, but is instead viewed as a formality to funnel patients into whatever they want to do to treat them.

I’ve said it before, and I’ll say it again, though: The central mystery behind Burzynski is how he’s gotten away with what he’s gotten away with for nearly 37 years. It is the single question about Burzynski whose answer I want to know more than the answer to any other question about him before I shuffle off this mortal coil. Why does the FDA keep investigating him, finding serious violations, and giving him, in essence, a slap on the wrist? Since 2000, he’s been investigated multiple times, and he’s received FDA warnings for his violation of human subjects regulations. True, this is the first time since the 1990s that the FDA has taken substantive action against him, issuing a partial clinical hold that appears unlikely to be lifted any time soon, if ever. Still, I’m worried. If Burzynski comes up with a response that satisfies the FDA, he could conceivably have his same old bogus trials resurrected yet again. Why doesn’t the FDA shut down any clinical trials done by the BRI and Burzynski Clinic permanently? Why doesn’t it at least shut down the BRI IRB, which would have the effect of shutting down the Burzynski Clinic because no reputable IRB would ever approve the clinical trials that Burzynski proposes? To get its scientifically dubious clinical trials approved, Burzynski needs an IRB run by an old crony of his from Baylor (Carleton Hazelwood) who just so happens to be the chairman of the board of the BRI, a massive conflict of interest. Any other IRB with so many repeated violations and such a massively obvious conflict of interest would be shut down. Any other research institute with so many violations of FDA regulations would not be allowed to do clinical trials of any kind.

Yet the BRI persists. No matter how many times the FDA investigates it, no matter how many warning letters the FDA sends it, the BRI continues. In the 1990s, a powerful Congressman, Rep. Joe Barton, put serious pressure on the FDA through public hearings, the public dressing down of then-FDA director David Kessler, and who knows what behind-the-scenes pressure tactics to let Burzynski open clinical trials of antineoplastons. As Burzynski’s own lawyer put it, those trials were “all an artifice, a vehicle we and the FDA created to legally give the patients Burzynski’s treatment.” Since the FDA folded in response to Barton’s pressure in the 1990s, I haven’t heard news of Barton applying pressure to the FDA again over its investigations of Burzynski. True, the Republicans were in the minority during four years of the period since then, but even after they won the House back in 2010 I haven’t heard of any political pressure being brought to bear on the FDA. So I wonder: Is the FDA still so cowed from its previous experience that it can’t just pull the plug and shut Burzynski down completely?